Receptors of the tumor necrosis factor receptor (TNFR) superfamily are expressed on a wide variety of cell types, and deliver many and diverse signals affecting cell activation, differentiation, and programmed cell death. Understanding how these receptors deliver cell signals, and how this process is regulated, is important to both basic knowledge about this large and multifunctional group of receptors, as well as how these signaling pathways can be manipulated to combat autoimmune disease, malignancy, and infection. The proposed project builds upon the progress made during the present funding of this grant, to examine how the TNFR family member CD40 regulates signaling to B lymphocytes. The present proposal extends our investigations to additional members of the TNFR superfamily, including CD120b (TNFR2), CD27, and the receptors for BAFF; and to an understudied TRAF in B lymphocytes, TRAF5. The proposed experiments also investigate the potential receptor, cell type, and species specificity of receptor-induced TRAF degradation, a key regulatory mechanism for TNFR family signaling. Because all cells, particularly immune cells, express many TNFR superfamily members simultaneously and/or sequentially, we also wish to examine the mechanisms and consequences of receptor interactions in determining biological outcomes of cell signaling. Three Aims are proposed: Aim 1. To understand the regulation of TRAF degradation by members of the TNFR superfamily; Aim 2. To examine how the molecular mechanisms of interactions between TNFR family members with each other and other key B cell receptors regulate B cell activation, survival and apoptosis; Aim 3. To explore the role of TRAF5 in B cell activation.